Traumatic brain injury (TBI) is associated clinically with progressive cognitive decline and dementia and pathologically with axonal injury and the deposition of multiple aggregated proteins. Repetitive mild TBI can trigger chronic traumatic encephalopathy (CTE), a unique tauopathy, and single TBI can provoke an Alzheimer's-like neurodegeneration. Unfortunately, the only way to diagnose these posttraumatic neurodegenerations, including CTE, is by post-mortem brain examination. In order to conduct prospective research into the incidence, prevalence, risk factors, clinical course, and ultimately, treatment for posttraumatic neurodegeneration, consensus criteria for diagnosis as well as objective biomarkers for disease must first be established. This initiative will assemble a multicenter team of expert neuroscientists to evaluate the late effects of TBI, including single and repetitive TBI of varying severity, and CTE, using histological examination of postmortem bio specimens and neuroimaging tools as a foundation to develop in vivo diagnostics. As a first aim, this proposal will bring together a team of 5 accomplished neuropathologists in neurodegenerative disease to establish consensus criteria for the post-mortem diagnosis of CTE. This team will also define the stages of CTE pathology, the features that differentiate CTE from other neurodegenerations and the effects of substance abuse, and the characteristics of posttraumatic neurodegeneration after single TBI. As a second aim, this proposal will establish a national bio specimen and data bank for TBI (Understanding Neurological Injury and Traumatic Encephalopathy (UNITE) bio bank) by developing a nationwide brain donor registry and hotline to acquire high quality bio specimens and data. The UNITE bank will use strictly standardized protocols and a web-based interface to ensure that tissue and data are readily available to qualified investigators. Comprehensive retrospective clinical data including clinical symptoms, brain trauma and substance abuse history, and medical records (including common data elements) will be entered into a secure database. Behavioral/ mood dysfunction, cognitive changes, substance abuse and traumatic exposure will be correlated with quantitative assessment of the multifocal tauopathy, Ass deposition and axonal injury. As a third aim, neuroimaging signatures of the neuropathology will be determined in post-mortem tissue using high spatial resolution diffusion tensor imaging (DTI) and autoradiography using a highly selective PET ligand for tau. Quantitative assessment of axonal injury, tau, and Ass will be correlated with ex vivo DTI abnormalities and tau ligand autoradiography. Pilot neuroimaging studies of individuals at high risk for the development of CTE will also be conducted in the final 2 years of the proposal. This proposal will determine the clinical and neuroimaging correlates of CTE and posttraumatic neurodegeneration and create the groundwork for establishing their incidence and prevalence. This study will have a tremendous impact on public health of millions of Americans and greatly increase our understanding of the latent effects of brain trauma.